BK channels mediate a novel ionic mechanism that regulates glucose-dependent electrical activity and insulin secretion in mouse pancreatic β-cells

摘要

BK channels are large unitary conductance K⁺ channels cooperatively activated by intracellular calcium and membrane depolarisation. We show that BK channels regulate electrical activity in β-cells of mouse pancreatic islets exposed to elevated glucose. In 11.1 mm glucose, the non-peptidyl BK channel blocker paxilline increased the height of β-cell action potentials (APs) by 21 mV without affecting burst- or silent-period durations. In isolated β-cells, paxilline increased AP height by 16 mV without affecting resting membrane potential. In voltage clamp, paxilline blocked a transient component of outward current activated by a short depolarisation, which accounted for at least 90% of the initial outward K⁺ current. This BK current (IBK) was blocked by the Ca²⁺ channel blockers Cd²⁺ (200 μm) or nimodipine (1 μm), and potentiated by FPL-64176 (1 μm). IBK was also 56% blocked by the BK channel blocker iberiotoxin (100 nm). IBK activated more than 10-fold faster than the delayed rectifier IKv over the physiological voltage range, and partially inactivated. An AP-like command revealed that IBK activated and deactivated faster than IKv and accounted for 86% of peak IK, explaining why IBK block increased AP height. A higher amplitude AP-like command, patterned on an AP recorded in 11.1 mm glucose plus paxilline, activated 4-fold more IKv and significantly increased Ca²⁺ entry. Paxilline increased insulin secretion in islets exposed to 11.1 mm glucose by 67%, but did not affect basal secretion in 2.8 mm glucose. These data suggest a modified model of β-cell AP generation where IBK and IKv coordinate the AP repolarisation.